1. Field of the Invention
The invention relates to contrast agents for magnetic resonance imaging. The invention also relates to methods for preparing the contrast agents.
2. Description of the Related Art
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the excited nuclei in the tissue attempt to align with this polarizing field, but process about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B1) that is in the x-y plane and that is near the Larmor frequency, the net aligned moment, Mz, may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetic moment Mt. A signal is emitted by the excited nuclei or “spins”, after the excitation signal B1 is terminated, and this signal may be received and processed to form an image.
In magnetic resonance imaging (MRI) systems, the excited spins induce an oscillating sine wave signal in a receiving coil. The frequency of this signal is near the Larmor frequency, and its initial amplitude, is determined by the magnitude of the transverse magnetic moment Mt. The amplitude, A, of the emitted NMR signal decays in an exponential fashion with time, t. The decay constant 1/T*2 depends on the homogeneity of the magnetic field and on T2, which is referred to as the “spin-spin relaxation” constant, or the “transverse relaxation” constant. The T2 constant is inversely proportional to the exponential rate at which the aligned precession of the spins would dephase after removal of the excitation signal B1 in a perfectly homogeneous field. The practical value of the T2 constant is that tissues have different T2 values and this can be exploited as a means of enhancing the contrast between such tissues.
Another important factor that contributes to the amplitude A of the NMR signal is referred to as the spin-lattice relaxation process that is characterized by the time constant T1. It describes the recovery of the net magnetic moment M to its equilibrium value along the axis of magnetic polarization (z). T2 relaxation is associated with a decrease in spin coherence, and T1 relaxation occurs due to a paramagnetic shift at the probe site and subsequent exchange of bound protons with the surrounding bulk water. The T1 time constant, which is referred to as the “spin-lattice relaxation” constant or the “longitudinal relaxation” constant, is longer than T2, much longer in most substances of medical interest. As with the T2 constant, the difference in T1 between tissues can be exploited to provide image contrast.
The reciprocals of these relaxation time constants are termed relaxation rates and denoted R1 and R2 where R1=1/T1 and R2=1/T2.
Contrast agents are exogenous molecules or materials that can alter the relaxation properties of tissue and induce image contrast. Contrast agents are typically paramagnetic, superparamagnetic, or ferromagnetic materials. Contrast agents are also sometimes referred to as imaging probes.
The extent to which a given contrast agent can alter the relaxation rate is termed relaxivity. Relaxivity is defined as the difference in the relaxation rate of a sample measured with and without the contrast agent. This relaxation rate difference is then normalized to the concentration of the contrast agent. Relaxivity is expressed as a lowercase “r” with a subscript “1” or “2” which refers to either the longitudinal or transverse relaxivity respectively. For instance longitudinal relaxivity, r1, is defined as r1=)(R1−R10/C where R1 is the relaxation rate in s−1 measured in the presence of the contrast agent, R1° is the relaxation rate in s−1 measured in the absence of contrast agent, and C is the concentration in mM of the contrast agent. Relaxivity has units of mM−1s−1. For contrast agents that contain more than one metal ion, relaxivity can be expressed in terms of the metal ion concentration (‘per ion’ or ‘ionic relaxivity’) or in terms of the molecular concentration (‘per molecule’ or ‘molecular relaxivity’). Relaxivity is an inherent property of contrast agents.
In an effort to elicit clinically-desired contrasts, MRI contrast agents have been developed that are designed to affect the relaxation periods. Not surprisingly, there are contrast agents that are used clinically to adjust T1 contrast and those that are used clinically to adjust T2 contrast.
T1-weighted (T1w) imaging provides image contrast where tissues or regions of the image are bright (increased signal intensity) when the T1 of water in that region is short. One way to increase image contrast is to administer a paramagnetic complex or material based on gadolinium (Gd), manganese (Mn), or iron. This paramagnetic contrast agent shortens the T1 of water molecules that it encounters and results in positive image contrast. The degree to which a given concentration of contrast agent can change T1 is the relaxivity as noted above. Compounds that have higher relaxivity provide greater T1w signal enhancement than compounds with low relaxivity; alternatively a high relaxivity compound can provide equivalent signal enhancement to a low relaxivity compound but at a lower concentration than the low relaxivity compound. Thus, high relaxivity compounds are desirable because they enable greater enhancement of lesions and improve diagnostic confidence; alternately, they can be used at lower doses and thus improve the safety margin of the contrast agent.
The majority of magnetic resonance contrast agents in clinical use employ the gadolinium ion in the +3 oxidation state. The manganese ion in the +2 oxidation state can also serve as a T1 relaxation agent. Mangafodipir (sold under the brand name Teslascan as mangafodipir trisodium) is a contrast agent delivered intravenously to enhance contrast in magnetic resonance imaging (MRI) of the liver. It includes paramagnetic manganese (II) ions and the chelating agent fodipir (dipyridoxyl diphosphate). The manganese shortens the longitudinal relaxation time (T1), making the normal tissue appear brighter in a magnetic resonance image. Mn-based agents having relaxivities as high as Gd-based contrast agents have also been described (see, e.g., Inorg Chem 43:6313-23, 2004).
One disadvantage of gadolinium magnetic resonance contrast agents is that the gadolinium ion is only stable in the +3 oxidation state under physiological conditions. Additionally, there is well-established connection between the usage gadolinium based contrast agents in renally impaired patients and a rare but serious fibrotic disorder termed nephrogenic systemic fibrosis (NSF),
Further advancement of manganese based magnetic resonance contrast agents would be of tremendous utility in contrast enhanced applications. Manganese can assess numerous oxidation states under physiological conditions, with the +2 oxidation state best suited for T1 and T2 contrast. This can be useful in the non-invasive study of tissue redox dynamics. Manganese based contrast agents could also represent a viable alternative to gadolinium in patient groups at increased risk for NSF.